Mitchell W. Krucoff MD, FACC Combo: A Combination of Sirolimus-Eluting Biodegradable Polymer and Anti-CD34 Antibody Coated Stent Mitchell W. Krucoff MD, FACC Professor of Medicine / Cardiology Duke University Medical Center Director, Cardiovascular Devices Unit Duke Clinical Research Institute

Disclosure of Conflicts No personal stock, holdings or IP No corporate revenue >$50k per annum Research grants, consulting relationships: Abbott Vascular Acist Medical Biosensors Boston Scientific Cook Medical Cordis J&J CSI Medtronic OrbusNeich St. Jude Medical Terumo

DES: Unmet medical needs & stent “healing” Short DAPT: High bleeding risk Non-compliant 30 day vs 3 month VLST & extended duration of DAPT Thrombotic lesions (ACS, STEMI)

The COMBO Plus Dual Therapy Stent: Traditional DES with biological therapy CD34 Antibodies Enable active capture of EPC for fast endothelial coverage Sirolimus & Polymer Matrix Drug and bioabsorbable polymer matrix for control proliferation Stent & Delivery System Highly conformable stent with excellent radial strength

CD34 antibodies capture circulating EPCs who mature into functional endothelium Following implantation, the immobilized CD34 antibodies are exposed to the circulating blood Circulating endothelial progenitor cells (EPC) are captures by antibody EPCs attach and differentiate into mature endothelial cells; an important step in re-establishing healthy neointima

Stent Surface Coverage by SEM in Stented Porcine Coronary Arteries Genous 3 Days 14 Days CD34/Cypher Cypher Several years ago, when the risk of late stent thrombosis associated with drug eluting stents was brought to light, we were challenged to apply our “Pro-Healing” immobilized anti-CD34 antibody technology to commercial DES to see if we could influence their healing behavior. In a series of published experiments in collaboration with CVPath and CRF, we applied the antibody treatment to commercial DES and then implanted them in porcine coronary arteries. Here on the left, you can see that at three days follow up, the antibody coated stent had the best tissue coverage while the DES showed minimal tissue with spotty protein coverage, and the DES coated with antibody was intermediate. At 14 days as seen on the right, the effect is even more pronounced, where the antibody coated stent was completely covered with tissue, the DES very poorly covered still with predominant protein material and sparce cells, while the antibody DES was intermediate and well on the way to being completely covered. Nakazawa G et al., JACC Cardiovasc Interv. 2010 Jan;3(1):68-75.

Confirmation of Coverage in Rabbit Model Percent Stent endothelialization (sEM) at 28 days EES p < 0.038 96.6% 78.5% COMBO Quantification of stent strut coverage (by sEM) showed a significantly improved endothelialization of the COMBO stent (96.6±3.5%) compared to the EES (78.5±16.8%; p=0.038) Ellenbroek, G.H., et al., AsiaIntervention, 2016. 2(2): p. 132-140.

REMEDEE: FIM 183 pts 2:1 RCT Combo vs. Taxus Liberte 1o endpoint: 9 mos LLL Haude M et al, JACC CV Int 6(4), 2013

Lesion Characteristics c/o Robbert J de Winter, MD PhD FESC Multivessel disease (>1 vessel, >70%) 21.1% Treated lesions (n=1511) Left main 1.3% LAD 50.6% LCx 20.2% RCA 26.1% Bypass graft 1.8% Number of vessels treated One vessel PCI 89.5% Multivessel PCI 10.5% AHA/ACC lesion type A 16.4% B1 24.9% B2 37.5% C 21.1% TIMI flow pre-procedure 14.5% 1 4.5% 2 9.8% 3 71.3% 50% } One Year Results REMEDEE Registry TCT 2015

Putting the results into perspective: 1-year results of ‘All Comers’’ REMEDEE Registry TWENTE DUTCH PEERS LEADERS COMBO Resolute Xience V Promus BioMatrix Cypher N 1000 697 694 906 905 857 850 TLF (%) 5.7 7.9 6.8 6.0 5.0 6.5 7.4 TV-MI (%) 0.7 4.6 2.0 1.0 5.8 Cardiac Death (%) 1.7 1.4 2.1 2.7 iTLR (%) 4.4 5.1 Definite ST (%) 0.5 0.6 0.0 0.3 Probable ST (%) 0.1 1.2 0.2 0.8 Source: P. Woudstra et al. J Am Coll Cardiol Intv. 2016; 9(11):1127-1134.

REMEDEE Registry Results 2-Year Clinical Results D. Kalkman et al. Poster presentation 2016 TCT.

Pivotal DES registration data: Japan & USA 572 pts 1:1 RCT vs Pivotal DES registration data: Japan & USA 572 pts 1:1 RCT vs. EES 1 year clinical & angio follow up Includes MV CAD and non-STEMI ACS FFR guided repeat revascularization OCT subgroups: 6 month & 1 year strut coverage Sites: Japan & USA Trial Structure: Sponsor: OrbusNeich International Pis: Shigeru Saito & Mitch Krucoff Japan & USA Pis: Shigeru Nakamura & Roxanna Mehran Study Chair: David F. Kong Coordinating Center: DCRI Site Monitoring: CMIC (Japan) & DCRI (USA) Angio Core Lab: CRF (Philippe Genereux) OCT Core Lab: CRF (Akiko Maehara) FFR Core Lab: Case Western (Hiram Bezerra) Uchida T et al, Circulation Journal 2013

ClinicalTrials.gov identifier: NCT02073565 HARMONEE Study Design Enrollment Completed Study Objective To demonstrate the effectiveness of COMBO vs. Xience in the treatment of significant ischemic heart disease, including UA and NSTEMI patients Primary Endpoint Ischemia & FFR driven TVF at 1 Year, where TVF defined as cardiac death, tv-MI, or ischemia- driven TVR Principal Investigators Mitch Krucoff, MD, Duke UMC Durham, NC, USA Shigeru Saito, Shonan Kamakura General Hospital, Kamakura, Japan ClinicalTrials.gov identifier: NCT02073565

OCT Measurement Methodology: EPC Mechanistic Surrogate Healthy tissue coverage: Independent , blinded Core Laboratory (Akiko Maehara, CRF) Per strut , per frame, and per patient analysis Combo superiority to EES

Leaving “occulo-stenotic” PCI Behind for Pivotal Trials Physiologic & High Resolution Anatomic F/U Fractional Flow Reserve (FFR): All patients at 1 year All “re-looks” Independent core lab (Hiram Bezerra, Case Western)

COMBO Dual Therapy Stent Clinical Trial Program Data available at TCT 2017 5-Year completed 36-Month completed 12-Month completed 24-Month completed Clinical FUP ongoing Enrollment completed Enrollment completed Enrollment completed Enrollment completed 6,000+ Patients planned in clinical trials Primary endpoint completed Enrollment completed

COMBO Stent: Conclusions DES technology still evolving Unmet needs: Short DAPT for HBR pts Site healing & very late ST (long DAPT) Thrombotic (ACS) lesions “Pro-healing” DES design might answer unmet needs for CAD patients Next step: HARMONEE results in 2017!

Mitchell W. Krucoff MD, FACC Combo: A Combination of Sirolimus-Eluting Biodegradable Polymer and Anti-CD34 Antibody Coated Stent Mitchell W. Krucoff MD, FACC Professor of Medicine / Cardiology Duke University Medical Center Director, Cardiovascular Devices Unit Duke Clinical Research Institute